Skeletal muscle mass declines with advancing age. This skeletal muscle loss is a major cause of frailty in the elderly. Important questions in the study of aging are what the mechanisms of this loss of skeletal muscle are and whether it is reversible by therapeutic interventions. Previous studies using indirect measurements of whole-body protein synthesis have failed to elucidate the biochemical basis of age-related muscle wasting. The primary goal of this proposal is to determine the effect of aging on muscle protein synthesis. The secondary goal is to determine whether this process is reversible by resistance training. We will test the hypotheses that aging decreases IGF-I production in skeletal muscle and the effect of IGF-I on muscle protein is reduced in the elderly. We will measure (13C)leucine abundance in total protein and myosin of serial skeletal muscle biopsy samples obtained during continuous infusion of L-(1-13C)leucine. Fractional (total and myosin) protein synthesis rate will be calculated using (13C)ketoisocaproate as the precursor pool. A forearm technique using (ring-2H5)phenylalanine as a tracer will be used to estimate muscle protein breakdown and its relative contribution to whole body protein dynamics, to study the local effect of IGF-I on muscle protein synthesis and degradation, and to assess whether the elderly demonstrate resistance to IGF-I's anabolic effect. In order to assess the molecular basis for changes in myosin synthesis rates and distinguish between translational and pretranslational levels of regulation, we will compare changes in the fractional synthesis rate of myosin to the relative abundance of messenger RNA coding for myosin heavy chain in skeletal muscle biopsies. We will also measure total RNA per unit of skeletal muscle protein to assess the efficiency and capacity to synthesize proteins. To examine the effect of age on the rate of muscle protein synthesis we will first study 90 healthy subjects from three separate age groups20-30 yrs, 45-55 yrs and above 65 yrs. To determine the effect of resistance training on muscle protein synthesis in middle-age and older subjects, we will randomly assign 60 inactive middle-aged and older subjects to a 12-week resistance training program or nonexercising control group and study their muscle protein synthesis. These studies will provide new insights into the mechanism of muscle wasting and the influence of resistance training for use as a therapeutic intervention to reverse the age-related decline in skeletal muscle protein synthesis.